The present invention relates to combinations of certain diaryl tetrahydrofuran, diaryl tetrahydrothiophene, triazolobenzodiazepine or thienotriazolodiazepine derivatives with antihistamines and the use thereof to treat allergic reactions.
Several mediators possessing a broad spectrum of potent biological activities are released during allergic reactions. Prominent among these mediators are histamine, leukotrienes and platelet-activating factor (PAF).
Compounds which prevent the effects of the mediators are thus of interest in treating allergic reactions. For example, numerous antihistamines are known in the art. Chlorpheniramine, brompheniramine, clemastine, ketotifen, azatadine, loratadine, and terfenadine are examples of commercially available or soon to be available antihistamines.
Various compounds have been disclosed as PAF antagonists. For example, compounds of the formula Ia or Ib ##STR1## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are as defined below) are disclosed as PAF antagonists in Science, Vol. 226, p. 1454 (1984) and German Offenlegungsschrift 35 02 392 A1.
Compounds of the formula II ##STR2## (wherein R.sup.12 R.sup.13, Ar, Ar.sup.1 and X are as defined below) are also disclosed as PAF antagonists in Biftu et al., U.S. Pat. Nos. 4,539,332 and 4,595,693 and European Patent Application No. 0 154 887 A1.
Antihistamines have proven useful in the treatment of certain allergic disorders such as seasonal rhinitis. However, the antihistamine therapy is ineffective in such complex allergic disorders as asthma indicating that histamine is only one of several mediators released during an allergic response. Indeed, in guinea pigs, allergic bronchospasm appears to be composed of three distinct components, mediated separately be histamine, leukotrienes and PAF.
PAF shares with histamine the abilities to cause bronchospasm and vasopermeability. In addition, PAF induces non-specific bronchial hyperreactivity in man as well as in animals.
Touvay et al., 6th International Conference on Prostaglandins, Florence, Italy, Jun. 3-6, 1986, p. 914, disclose BN1267 and related compounds of the general formula ##STR3## which compounds are said to exhibit antihistaminic activity. The presentation also mentions that ". . . the association of this dose [10 mg/kg p.o.] of BN 1267 with a non-active dose of a specific PAF-receptor antagonist BN 52021 (-10% at 2 mg/kg p.o.) administered one hour before PAF-acether significantly antagonized the bronchospasm (-45% p &lt;0.01)." BN 52021 is ginkgolide B having the structure: ##STR4##
While we have found that representative examples of the above PAF antagonists prevent PAF-induced lethality, we have also found that they do not provide protection against allergic death (anaphylactic shock) in sensitized mammals, such as ovalbumin sensitized mice. Antihistamines such as chlorpheniramine, clemastine and ketotifen provided only partial protection against ovalbumin-induced lethality.